Seasonal influenza causes significant morbidity and mortality. Annual immunization with a trivalent inactivated vaccine (TIV) is recommended. However, despite improved vaccination coverage in older adults over time, influenza-related mortality has actually increased. While many TIV studies indicate its benefit for older adults as a whole, these studies lacked representation of the older and frail subset of the elderly who suffer over three-quarters of influenza-related mortality. Our pilot study funded by a Beeson K23 award showed significant TIV failures in both antibody response to TIV and clinical protection in the frail elderly. Chronic CMV infection is highly prevalent in older adults based on anti-CMV IgG serology. A large body of literature suggests that chronic CMV infection contributes to T-cell immunosenescence and mortality. However, anti-CMV IgG serology is a crude measure that merely indicates prior exposure to CMV and does not distinguish chronic (persistent) from past (resolved) infections. We have recently developed a highly sensitive and specific nested PCR-based assay for the detection of CMV DNA in peripheral blood mononuclear cells (PBMCs) in older adults. Our data indicate that CMV DNA is present in only about 60% of CMV seropositive older adults and that CMV DNA positivity, rather than IgG titer, is associated with increased CMV-specific CD8+ T cells and heightened chronic immune activation. Based on these published pilot studies and preliminary data described in this application, our overall hypothesis is that chronic CMV infection as defined by the presence of CMV DNA in PBMCs contributes significantly to TIV failure in adults over 75. We propose a prospective 4-yr TIV immunization study in community-dwelling adults over 75 with the following 3 aims: 1) Test the hypothesis that CMV DNA positivity leads to increased rates of post-vaccination Influenza-like illness (ILI) and influenza infection. ILI cases will be identified by post-vaccination surveillance and respiratory specimens will be tested using the cutting edge PCR-based IBIS assay which can accurately subtype influenza and other respiratory viruses. As a secondary aim, we will also explore whether the effects of chronic CMV infection on ILI and influenza infection vary by frailty status; 2) Test the hypothesis that CMV DNA positivity leads to impaired strain-specific antibody responses to TIV; and 3) Test the hypothesis that CMV DNA positivity leads to restricting homotypic and heterotypic T-cell responses to influenza viruses at baseline and after TIV immunization. Upon completion, this study will help define the role of chronic CMV infection in TIV failure and its underlying humoral and T-cell immune mechanisms in the vulnerable subset of the elderly population, which has been underrepresented in previous vaccine studies. The 4-year study design is necessary to account for seasonal variations in influenza epidemics and the potential for antigenic mismatch in a given year. The ultimate goal of this research is to strengthen immune protection against influenza for vulnerable older Americans through prevention and mitigation of chronic CMV infection.